PB2296: ROBUST BRUTON’S TYROSINE KINASE (BTK) DEGRADATION WITH NX-5948, AN ORAL BTK DEGRADER, IN A FIRST-IN-HUMAN PHASE 1A TRIAL IN PATIENTS (PTS) WITH RELAPSED/REFRACTORY B CELL MALIGNANCIES
Authors: Kim Linton, Francesco Forconi, David Lewis, John Riches, Dima El-Sharkawi, Mary Gleeson, Sarah G Injac, Srinand Nandakumar, May Tan, Ganesh Cherala, Graham P Collins
Journal: HemaSphere (2023)

Topic: 19. Aggressive Non-Hodgkin lymphoma - Clinical Background: Although BTK inhibitors are widely used for treating B cell malignancies, acquired resistance mutations can reduce or eliminate their efficacy and represent a growing clinical challenge. Novel mutations were recently described to confer clinical resistance to non-covalent BTK inhibitors and abolish BTK kinase activity while retaining intact BCR signaling and BTK-dependent growth, indicating that mutant BTK elicits scaffold-mediated function that drives malignant B cell survival [Wang et al. N Engl J Med 2022]. NX-5948 is a novel oral small molecule that induces BTK degradation via recruitment of the cereblon E3 ligase complex. NX-5948 is being evaluated as treatment for tumors that have developed resistance to covalent and/or non-covalent BTK inhibitors or in B cell indications where treatment with BTK inhibitors has been less effective. NX-5948 induces sub-nanomolar potency degradation of both wild-type and known mutant forms of BTK in vitro [Noviski et al. AACR 2023], demonstrating rapid in vivo degradation in mouse and non-human primate B cells within two hours of oral administration [Robbins et al. ASH 2021]. In addition to efficacy in subcutaneous tumor models, NX-5948 can cross the blood-brain barrier and degrade BTK intracranially, translating to preclinical efficacy in brain lymphoma disease models [Robbins et al. ASH 2021]. Aims: Here we report preliminary PK/PD findings from the first-in-human phase 1a trial of NX-5948 in pts with B cell malignancies. Methods: NX-5948-301 is a first-in-human, dose-escalation (phase 1a) and cohort-expansion (phase 1b) study designed to evaluate the safety, tolerability, and clinical activity of NX-5948 in adult pts with relapsed/refractory B cell malignancies (NCT05131022). Phase 1a will evaluate safety and tolerability of NX-5948 in pts with relapsed/refractory CLL, SLL, non-GCB DLBCL, FL, MCL, MZL, and WM, including those with secondary CNS involvement in any disease indication listed as well as PCNSL. Key eligibility criteria include: ≥2 prior lines of therapy; measurable or other evaluable disease per indication specific response criteria; and an ECOG PS of 0–1. NX-5948 is given orally, once daily, with dose escalation according to a standard 3 + 3 design. Approximately 110 pts (30 in phase 1a, 80 in phase 1b) may be enrolled and treated until confirmed disease progression or unacceptable toxicity. Pharmacokinetic parameters are generated using non-compartmental analysis. Pharmacodynamic biomarkers are assessed in whole blood longitudinally using a 10-color flow cytometry assay designed to quantify BTK. Results: As of Dec 1, 2022, 7 pts have been enrolled in phase 1a and received NX-5948 at 50 mg (n=4) or 100 mg (n=3). Baseline demographics/disease characteristics: median age 59.0 (range 46.0–79.0) years; male/female 57.1%/42.9%; white 100%; ECOG PS 0/1 42.9%/57.1%; median time since diagnosis 7.6 (range 2.9–23.5) years. Primary diagnosis: DLBCL (n=2), MCL (n=2), MZL (n=2), FL (n=1). Most pts (n=6) have received ≥4 prior lines of therapy. NX-5948 exhibited dose-proportional PK, with a half-life of ~12 hours, and a Tmax of 2–3 hours. Rapid, robust and sustained BTK degradation was observed in all pts dosed, regardless of their absolute BTK starting level, tumor type, or dose level of NX-5948 (see figure). Summary/Conclusion: Preliminary findings suggest that NX-5948 exhibits dose-proportional PK and supports daily dosing, resulting in rapid, robust and sustained BTK degradation. Additional indications, including CLL, and additional dosing levels are currently being explored.Keywords: Bruton’s tyrosine kinase inhibitor (BTKi), B cell